Is Highly Heterogeneous in Primary Cervical Screening in Amazonian Peru

12 Pages·2015·0.49 MB·English

RESEARCHARTICLE
Visual Inspection after Acetic Acid (VIA) Is
Highly Heterogeneous in Primary Cervical
Screening in Amazonian Peru
MaribelAlmonte1,2*,CatterinaFerreccio3,SilvanaLuciani4,MiguelGonzales5,Jose
M.Delgado5,CarlosSantos6,ManuelAlvarez6,JackCuzick2,PeterSasieni2
1InternationalAgencyforResearchonCancer,Lyon,France,2CentreforCancerPrevention,Wolfson
InstituteofPreventiveMedicine,QueenMaryUniversityofLondon,London,UnitedKingdom,3Advanced
CenterforChronicDiseases,ACCDIS-FONDAP,FacultaddeMedicina,PontificiaUniversidadCatólicade
Chile,Santiago,Chile,4PanAmericanHealthOrganization(PAHO),Washington,DC,UnitedStatesof
America,5DirecciónRegionaldeSaludSanMartín,SanMartín,Perú,6InstitutoNacionaldeEnfermedades
Neoplásicas,Lima,Perú
* [email protected]
Abstract
OPENACCESS
Citation:AlmonteM,FerreccioC,LucianiS,
GonzalesM,DelgadoJM,SantosC,etal.(2015) Background
VisualInspectionafterAceticAcid(VIA)IsHighly
HeterogeneousinPrimaryCervicalScreeningin Conventionalcytology(Pap)andvisualinspectionaftertheapplicationofaceticacid(VIA)
AmazonianPeru.PLoSONE10(1):e0115355. arecurrentlyusedinprimaryscreeninginPeru.StudiessuggestthatthequalityofVIAis
doi:10.1371/journal.pone.0115355
highlyvariable.Over36000womenwerescreenedwithPapandVIAintheTATI(Tamizaje
AcademicEditor:Jian-XinGao,ShanghaiJiaoTong yTratamientoInmediatodeLesionesCervico-uterinas)projectconductedinAmazonian
UniversitySchoolofMedicine,CHINA
Peru.Withinanestedstudytocompareseveralscreeningtechniques(C-TATI),atotalof
Received:June23,2014 5435womenwereadditionallyscreenedwithliquid-basedcytology(LBC)andhigh-risk
Accepted:November22,2014 humanpapillomavirustesting(HR-HPV).Weinvestigatethevariationofpositivityratesof
VIA,Pap,LBCandHR-HPVinC-TATIandofVIAinthefullTATIintervention.
Published:January30,2015
Copyright:©2015Almonteetal.Thisisanopenac-
Methods
cessarticledistributedunderthetermsofthe
CreativeCommonsAttributionLicense,whichpermits Atthescreeningvisit,midwivescollectedthreecervicalsamplesforPap,LBCandHC2be-
unrestricteduse,distribution,andreproductioninany foreperformingVIA.Thedispersionfactor“D”(D=Pearsonchi-squarevalue/degrees-of-
medium,providedtheoriginalauthorandsourceare
freedom)wasusedtomeasurethevariabilityoftestsresults.WithinC-TATI,thevariability
credited.
ofpositivityratesofVIA,Pap,LBCandHR-HPVwasalsographicallyassessedwithbox-
DataAvailabilityStatement:Relevantdataarewith-
andscatterplotsbymidwifeandmonthofscreening.Funnelplotsandsmoothedscatter
inthepaperanditsSupportingInformationfiles.
plotswereusedtocorrelatethevariationofVIAbythenumberofexaminationsperformed
Funding:TheTATIprojectwasconductedwiththe
byeachmidwifeoverthefullTATIintervention.
generoussupportoftheBill&MelindaGatesFounda-
tiontothePanAmericanHealthOrganizationthrough
theAllianceforCervicalCancerPrevention.Cancer Results
ResearchUKprovidedfinancialsupportfortheaddi-
ConsistentlyoverTATI,VIAresultswerehighlyvariable,independentlyoftheexaminer,the
tionalworkinvolvedinthisstudyincludingthecostof
HPVandLBCtesting. timewhenthetestwasperformedandthenumberofteststheexaminerperformed(D>6,
p-values<0.001).InC-TATI,VIAresultsvariedthemostwhilethoseofHR-HPVvariedthe
CompetingInterests:Theauthorshavedeclared
thatnocompetinginterestsexist. least(Ds>25,p-values<0.001forVIA,Ds<1.6,p-values>0.05forHR-HPV).Noevidence
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VariationofVIAinCervicalScreeninginPeru
forcorrelationbetweenthenumberofVIAsdonepermidwifeandthevariabilityofVIAre-
sultswasobserved.
Conclusion
Thelackofover-dispersionforHR-HPVdetectionsuggeststhatthevariableVIAresultsdo
notreflecttruevariationinunderlyingdisease,butalackofconsistencyinhuman
judgement.
Introduction
Cervicalcanceristhefourthmostcommonfemalecancerintheworld[1].Cervicalscreening
usingconventionalcytology(Pap)hashadanimpactoncervicalcancerratesinmanydevel-
opedcountriesbutnotinthedevelopingworld[2,3].
Ithasbeenestablishedthatinfectionwithhigh-risktypesofhumanpapillomavirus(HPV)
isanecessarycauseforcervicalcancer[4].Bothhigh-riskHPVdetectiontests(HR-HPV)and
prophylacticvaccineshavebeendevelopedandHPVvaccinationprogrammestargetingyoung
girlshavebeenestablishedallovertheworld.However,itwilltakeseveraldecadestoseethe
impactofHPVvaccination,hence,cervicalscreeningshouldcontinue.HPVtestingwithcytol-
ogytriagemayreplacecytologyscreeningsoonwithinorganisedscreeningprogrammeswith
good-qualitycytology.
Thequestionofhowbesttoscreenpopulationswithdifficultornoaccesstohealthcarere-
mainsunanswered.Visualinspectionaftertheapplicationofaceticacid(VIA)followedby
treatmentwithcryotherapyhasbeenproposedasanalternativescreeningapproachinthese
settings.However,resultsfromstudiesevaluatingtheperformanceofVIAhavebeeninconsis-
tent.Inparticular,severalstudiesconductedinIndiaandAfricahavereportedbetterVIAre-
sultsthanthoseofLatinAmerica[5–10].TherecentlypublishedWHOguidelinesfor
screeningandtreatmentofprecancerouslesionsforcervicalcancerpreventionproposetheuse
ofHPVtesting,ifavailable,followedbyimmediatecryotherapyorbytriagewithVIAandthen
cryotherapy[11].Itisnowimportantnotonlytoevaluatetheperformanceofscreeningtests
butalsotoidentifywhichtestsaremorepronetosubjectivevariation(dependonproviders),
whichsufferwhenusedindifficultconditionsinplaceswithfewspecialistdoctorsandpoor
communications,andwhichcanbeusedinsimplealgorithmstoensurethatmostwomenwith
lesionsreceivedadequatetreatment.Over36000womenwerescreenedwithVIAandPapin
the“TamizajeyTratamientoInmediatodeLesionesCervico-uterinas”(TATI)projectinAma-
zonianPeru[12].Withinanestedstudythatcomparedseveralscreeningstrategies(C-TATI),
5435womenwereadditionallyscreenedwithliquid-basedcytologyandHR-HPV[7].Here,we
investigatethevariationofVIA,Pap,LBCandHR-HPVresultsinC-TATIandofVIAinthe
fullTATIintervention.
Methods
ThemethodsofTATIhavebeendescribedelsewhere[7,12,13].Briefly,36759womenaged
25–49yearsresidentsintheSanMartinregioninPeru,wereexaminedbyamidwife,whotook
acervicalsampleforaPapandperformedVIA,whichwasconsideredpositiveifanyaceto-
whitelesionwasobservedinorclosetothetransformationzoneandotherwisenegative.
WomenpositiveonVIAwereexaminedbyageneraldoctor,whoperformedmagnifiedVIA
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VariationofVIAinCervicalScreeninginPeru
(VIAM),tookbiopsiesandtreatedanymanageablelesionswithcryotherapyorreferred
womenforcolposcopyandfurthertreatment.
TATIwasconductedover36months.Duringthefirstthreemonths,thelogisticsofthe
screeningprocesseswerepiloted(months-3to0).Overthefollowing11months,acomparative
study(C-TATI,months1to11)inwhich5435womenwereadditionallyscreenedwithliquid-
basecytology(LBC)andhigh-riskHPVtesting(HR-HPV)donebyHybridCaptureII(hc2).
SimultaneouslyandupuntiltheendofTATI,womenwerescreenedwithonlyPapandVIA
(RestofTATI:R-TATI,months1to33).
PapandLBCreportedasASCUSorworse(PapASCUS,LBCASCUS)wereconsidered
positiveandthestandardthresholdof1(RLU/co)ofhc2wasusedtoidentifyHR-HPVpositive
samples.NoHPVgenotypingwasdoneinthisstudy.Cervicalintraepithelialneoplasiagrade2
orworse(CIN2+)wasthemaindiseaseoutcomeofthestudy.
VIAtraining
Initialtrainingwasofferedto19midwivesand12generaldoctorsonVIA[7,13].Thetraining
includedtheoreticalandpracticalsessionsonperformingVIAandcollectingcervicalsamples
forPap,generalaspectsoffemaleanatomy,cervicalcancerprevention,diagnosisandmanage-
mentofsexuallytransmittedinfectionsandcommunicationandcounsellingskills.Photo-
graphsofcerviceswerereviewedthroughoutthecourse.TraineespracticedVIAfirston
anatomicalmodelsandthenexaminedwomenunderdirectsupervisionoftrainers.General
doctorswereadditionallytrainedonVIAMandtreatmentwithcryotherapy.Atotalof42mid-
wivesand25doctorsweretrainedinTATIoverthreetrainingcoursesofoneweekeach.
Statisticalanalysis
Weusedthedispersionfactor(D)tomeasurethevariabilityofthescreeningtestsresultsbya
numberoffactors:age(infive-yearbands),midwifewhoperformedVIAandmonthofscreen-
ing,overallandseparatelybysub-study(C-TATIvs.R-TATI).Dwasdefinedastheratioof
thePearsonchi-squarevalueofa2xmtable(2=positiveornegative,m=numberoflevelsof
factorofinterest)dividedbythedegreesoffreedom(d.f.=n=m-1).Sincetheexpectedvalue
ofarandomvariableXwithachi-squaredistributionwith“n”d.f.is“n”,theexpectedvalueof
Dunderthenullhypothesisofequalunderlyingpropertiesineachstrataisapproximately1,
i.e.E(D)=E(X)/n=1.Thus,Dvaluesclosetozerowillrepresentminimaldispersion(lessthan
randomvariation)andhighestvaluesofD,furtheraboveunity,willrepresentoverdispersion.
Positivityrates(PR)ofVIA,PapASCUS,LBCASCUSandHR-HPVwerecalculatedover-
all,byage,bymonthofscreeningandbymidwifewhocollectedthesamplesandperformed
VIA.ThePRofeachmidwife(42differentVIAPRs)participatinginTATIwascalculatedin-
cludingtheresultsofallexaminationsperformedthroughouttheinterventionandgrouped
intoGroup1:VIAperformedby19midwiveswhoparticipatedinC-TATI(19VIAPRs)and
Group2:VIAperformedby23midwiveswhoparticipatedinR-TATIbutnotinC-TATI
(23VIAPRs).Asthe19C-TATImidwivesinGroup1screenedwomeninC-TATIandin
R-TATIinparallel(inalternativescheduledclinics),theirPRswerealsocalculatedseparately
forexaminationsdoneinC-TATI(19PRs)andR-TATI(19PRs).Next,theoverallPRwithin
eachgroupwascalculatedsumminguptheresultsofallVIAsperformedinthegroupwithcor-
respondingbinomial95%confidenceintervals(95%CI).Atestfortrendswasusedtocompare
VIAPRsovertime(year1=months1–11,year2:12–23,andyear3=24–33)inR-TATI.
WegraphicallyassessedthevariationofPRswith:1)boxplotstocomparethevariationof
PRsofscreeningtestsinC-TATI,2)error-barplotstosummarisethedifferencebetweenVIA
PRsperformedbythesamemidwifeduringthefirstyearofinterventioninC-TATIandR-TATI,
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VariationofVIAinCervicalScreeninginPeru
3)funnelplotstoevaluatetheextenttowhichthevariabilityofVIAresultscouldbeexplainedby
thenumberofexaminationsperformedbyeachmidwifeand4)smoothedscatterplotstoevalu-
atewhetherthevariabilityofVIAresultscouldbeexplainedbyalearningcurveandifsotoiden-
tifyaminimalnumberofVIAexaminationsrequiredtoobtainlessvariableresults[14].
BothfunnelplotsandsmoothedscatterplotsallowvisualisationofthevariationofVIAPRs
takingintoaccountthenumberofVIAsperformed.Funnelplotsweregraphedintwosteps:
1)scatterplotsofVIAPRsbythenumberofVIAsperformed,and2)funnelswith95%CIs
(controllimits)wereconstructedaroundtheoverallVIAPR.Inthesegraphs,theareaswithin
thecontrollimitsrepresenttheamountofvariationexpected.Thus,thehigherthenumberof
PRsoutsidethecontrollimits,themoreover-dispersedthedataare;andthemostcloselyclus-
teredthePRsaretotheoverallrate,thelessrandomvariation.Arunninglinewasusedto
smooththescatterplotsforeachmidwifeandobtainthesmoothedscatterplots.
AllstatisticalanalysesweredoneusingtheStatasoftware,version12.
EthicalConsiderations
TheTATIprojectwasapprovedbytheEthicalCommitteeoftheMinistryofHealthofPeru
andtheEthicsCommitteeofthePanAmericanHealthOrganization.Writteninformedcon-
sentwasobtainedfromallparticipantsbytrainedmidwives.
Results
Afterexcluding812VIAsperformedbydoctors,atotalof35947VIAswereperformedby42
midwivesover36months.Duringthepilotphaseoftheintervention,2108womenwere
screenedwithPapandVIA.Overthenext11months,19midwivesparticipatinginC-TATI
performed12515VIAexaminations,5401withinC-TATIand7114withinR-TATI;while568
VIAswereperformedbynineofthe23midwiveswhoonlyparticipatedinR-TATI.Once
C-TATIfinalised,VIAwasperformedin20756women(61%oftheseexaminationsweredone
bythe19C-TATImidwives).Fromhereon,resultsarebasedon33839womenwhowere
screenedbyamidwifeafterthepilotphase(Fig.1).
InC-TATI(n=5401),theoverallPRswere24.2%forVIA,2.1%forPapASCUS+,17.9%
forLBCASCUS+and12.6%forHR-HPVtesting.Eachofthesetestswerepositivein36(43%),
32(39%),64(77%)and79(95%)ofthe83CIN2+detectedcases.ThePRsofVIAand
HR-HPVtestingdecreasedwithincreasingagewhilethoseforPapandLBCincreasedwith
increasingage,mostlyduetoanincreasingtrendofmoderatedysplasiaandworseabnormali-
tiesbyage(allp-valuesfortrendswerehighlysignificant,S1Table).Fig.2showsboxplotsof
thevariationofPRsofscreeningtestsbymidwifeandovertime.VIAPRsvariedthemost
(D=27.8and27.7bymidwifeandovertime,p-values<0.001).Incontrast,HR-HPVtesting
wasthemosthomogeneoustest(D=1.5and0.7,p-values>0.05,respectively).PRsofLBC
ASCUS+alsovariedsignificantly(D=3.1and8.7,p-values<0.001)whilethoseofPapASCUS
+variedlittle(D=1.4and0.7,p-values>0.05).Aftertakingintoaccountthelowrateofdisease
detectedbyPap(S1Table),werepeatedtheanalysisoninadequaterates(IR)ofbothLBCand
Pap.ThistimethePapIRswerelargelymoreheterogeneous(D=29.0bymidwifeand12.2
overtime,p-values<0.001)thanLBCIRsandPRsofLBCandHR-HPV(datanotshown).We
alsorepeatedtheanalysisonpositivityratesofVIAandPapinR-TATI.Theresultsweresimi-
lar,VIAPRsweremoreheterogeneousthanPapsmearPRs,however,theresultsofbothtests
werehighlyvariable(datanotshown).
AsummaryofVIAPRspermidwifebygroupofmidwivesispresentedinTable1.Overall,
midwivesperformedbetween30and2346VIAs.Twomidwivesperformedlessthan100VIA
exams(onedid30,theother80),43performedbetween113and1962VIAseachandthe
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Figure1.DiagramoftheTATIprojectwiththenumberofvisualexaminationsperformedbymidwives
inthepilotphase(months-3–0),duringthetimeofthecomparativestudy(months1–11)andafterthe
comparativestudy(months12–33).VIA=Visualinspectionaftertheapplicationofaceticacid.C-TATI=
Comparativescreeningstudy(months1–11).R-TATI=restoftheTATIintervention(months1–33).
doi:10.1371/journal.pone.0115355.g001
remainingthreeover2000VIAs(2174,2256and2346,respectively).TheoverallVIAPRper
midwifeinGroup1was16%(95%CI:15.5%,16.5%)andwassignificantlylowerthanthatof
VIAperformedbymidwivesinGroup2(23.5%,95%CI:22.6%,24.4%).Incontrast,thedisper-
sionfactorofVIAresultsofmidwivesinGroup1wasalmostdoublethatofmidwivesin
Group2(D=48.2andD=27.0,p-values<0.001),althoughbothdispersionfactorswerehighly
significant.Theresultsdidnotchangeafterexcludingmidwiveswhoperformedlessthan100
ormorethan2000VIAexaminations.Surprisingly,thePRofmidwivesinGroup1wassignifi-
cantlyhigherwhentheyscreenedwomeninC-TATI(24.2%,95%CI:23.1%,25.4%)thanwhen
theyscreenedwomeninR-TATI(13.7%,95%CI:13.3%,14.2%),andhigherthantheoverall
PRofallmidwivestogether(17.9,95%CI:17.5%,18.3%).Inviewoftheseresults,wecompared
PRsinC-TATIandR-TATIofthe19midwivesinGroup1byplottingthedifferencebetween
thetwopositivityrates(C-TATI—R-TATI)with95%CIs.Thedifferencewasnegative
(decreaseof0.4%)onlyforonemidwifewhiletheresthadhigherPRsinC-TATIthanin
R-TATI(meandifference:13.6%,95%CI:-10.9%,38.2%).Thus,midwivesassignedmorefre-
quentlyapositiveresultwithinC-TATIthanwithinR-TATI(S1Fig.).
Table2showstheVIAPRsofmidwivesbygroupandyearoftheintervention,whenthey
screenedwomenonlyinR-TATI.VIAPRsofmidwivesinGroup1wereconsistentlylower
thanthoseofmidwivesinGroup2(atleast7%differencebetweenoverallrates,statistically
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Figure2.BoxplotsofpositivityratesofVIA,HPV,LBCandPapandofinadequateratesofLBCand
PapinC-TATI.VIA=Visualinspectionaftertheapplicationofaceticacid.HPV=Humanpapillomavirus.
LBC=Liquid-basedcytology.C-TATI=Comparativescreeningstudy(months1–11).D=Dispersionfactor.
ASCUS+=Atypicalsquamouschangesofundeterminedsignificanceorworsecytologicalabnormalities.
Inad=Inadequate.
doi:10.1371/journal.pone.0115355.g002
significanteachyear).TherewasaconsistentincreasingtrendoftheoverallPRspergroup
ofmidwivesandinbothgroupscombinedfromthefirstyeartothesecondyear,andaconsis-
tentsmalldecreasefromthesecondtothethirdyear(p-for-trend<0.001).However,allDs
wereonceagainhighlysignificant.ItisworthnotingthatfivemidwivesinGroup2performed
lessthan50VIAsinthefirstyear,hencetherangeofVIAPRsvariedbetween0%and67%
(D=8.6).Afterexcludingextremevalues,theresultsdidnotchange(range:8.6%to39.5%,
D=12.5,p-value<0.001).
Insummary,independentlyofwhether:i)VIAwasperformedinC-TATIorinR-TATI,
ii)VIAwasperformedbymidwivesinGroup1orGroup2,oriii)VIAwasperformedinthe
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Table1.VariationofVIApositivityratespermidwifeoverthe33monthsoftheTATIinterventionbygroupofmidwives.
Groupofmidwifes(No.) No.womenscreened No.VIA/midwife %VIApositive/midwife Dispersionfactor1
Mean Range Overall(95%CI) Range
Group1(19)
C-TATI 5401 284.3 122–544 24.2(23.1–25.4) 6.8–58.2 27.8
R-TATI 19,748 1039.4 357–2063 13.7(13.3–14.2) 7.0–24.4 30.9
Allgroup1 25,149 1323.6 638–2346 16.0(15.5–16.5) 7.2–27.2 48.2
Group2(23)
R-TATI 8690 377.8 30–983 23.5(22.6–24.4) 7.1–43.4 27.0
Allmidwives(42) 33,839 554.7 30–2346 17.9(17.5–18.3) 7.1–43.4 43.0
C-TATI=Comparativescreeningstudy(months1–11).R-TATI=restoftheTATIintervention(months1–33).Group1:19midwiveswhoparticipatedin
C-TATIandR-TATI.Group2:23midwiveswhodidnotparticipateinC-TATI.95%CI=95%confidenceinterval.
1Alldispersionfactorswerehighlysignificant(p-value<0.001)
doi:10.1371/journal.pone.0115355.t001
first,secondorthirdyear;VIApositivityratesweresignificantlyandconsistentlyheteroge-
neous(D>7,p-values<0.001forallpossiblecombinations).
Fig.3ashowsthevariationofVIAPRsofeachofthe19Group1midwives(denotedbycap-
italletters“A”to“S”)whentheyscreenedwomeninC-TATI(left,ingreydiamonds)andinR-
TATI(right,inblackdiamonds).WithinC-TATI,fiveVIAPRswereabove35%(B,C,E,L
andN)andthreebelow10%(F,RandS)whileinR-TATIallrateswerebelow25%withsixof
thembelow10%(F,J,L,P,RandS).DespitetheapparentcorrelationofVIApositivitywith
thenumberofexamsdone(asmidwivesperformedmoreVIAs,theirPRsbecamemoretightly
clusteredaroundtheoverallVIAPR);themajorityofVIAPRsliedoutsidethe95%control
limitsandonlysix(A,G,J,K,MandO)inC-TATIandfive(A,E,H,MandO)inR-TATI
werewithintheexpectedrange.Therewasasubstantial43%reductionintheoverallVIAPR
withinR-TATIincomparisontoC-TATI,therefore;wedecidedtorepeatthisanalysis,includ-
ingallmidwivesperformingVIAonlyinR-TATI(Fig.3b).Thistime,Group2VIAPRs(de-
notedbysmallletters“a”to“w”)wereplottedingreysquaresandthoseofGroup1(denoted
byletters“A”to“S”)inblackdiamondsasinFig.3a.ThepatternofVIAPRsperformedinR-
TATIbymidwivesinGroup2whodidnotparticipateinC-TATI,wassomehowsimilarto
thatofVIAPRsinC-TATIshowninFig.3a.Thistime,theratesof13ofthe23midwivesin
Group2werelowerthan20%;however,onlyfivepositivityrateswerewithintheexpected
range(a,c,n,sandw).
Table2.VariationofVIApositivityratespermidwifebygroupofmidwivesandyearofinterventionwithinR-TATI.
GroupofMidwives Year1February-December Year2January-December Year3January-September
No.VIAa Mean %VIApositive/midwife Db No.VIAa %VIApositive/midwife Db No.VIAa %VIApositive/midwife Db
(No.Mid.) No.VIA Overall(95%CI) (No.Mid.) Overall(95%CI) (No.Mid.) Overall(95%CI)
Group1R-TATI 7114(19) 7114(19) 12.2(11.5–12.0) 7.4 6933(19) 15.0(14.2–15.8) 12.5 5701(18) 14.1(13.2–15.0) 17.5
Group2R-TATI 568(9) 568(9) 21.1(17.8–24.7) 8.6 3032(19) 27.1(25.6–28.8) 13.7 5090(21) 21.5(20.4–22.7) 20.7
All 7682(28) 7682(28) 12.9(2.2–13.7) 9.9 9965(38) 18.7(17.9–19.5) 19.3 10,791(39) 17.6(16.9–18.3) 21.9
R-TATI=restoftheTATIintervention(months1–33).Group1:19midwiveswhoparticipatedinC-TATIandR-TATI.Group2:23midwiveswhodidnot
participateinC-TATI.Mid.=Midwives.D=Dispersionfactor.95%CI=95%confidenceinterval.
aOverallnumberofVIAexaminationsperformedbymidwivesinthatgroupduringthatyear
bAlldispersionfactorswerehighlystatisticallysignificant(p-value<0.001)
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Figure3.FunnelplotsofthevariationofpositivityratesofVIAperformedbymidwivesover33
monthsoftheTATIintervention.C-TATI=Comparativescreeningstudy(months1–11).R-TATI=restof
theTATIintervention(months1–33).Group1:19midwiveswhoparticipatedinC-TATIandR-TATI.Group
2:23midwiveswhodidnotparticipateinC-TATI.PositivityratesofVIAperformedbymidwivesinGroup1
arerepresentedbycapitalletters“A”to“S”.PositivityratesofVIAperformedbymidwivesinGroup2are
representedbysmallletters“a”to“w”.
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Figure4.ProportionofVIAexamsreportedpositiveaccordingtothenumberofVIAexamscarried
outbymidwiveswhoperformed500ormoreVIAexamsthroughouttheintervention.ProportionofVIA
examsreportedpositivebymidwivesinGroup1arerepresentedbycapitallettersandthoseofmidwivesin
Group2bysmallletters.
doi:10.1371/journal.pone.0115355.g004
Fig.4showstheproportionofVIAsreportedpositiveovertime(i.e.accordingtothenum-
berofVIAscarriedout)foreachofthe25midwiveswhoperformedatleast500VIAs.Forin-
stancemidwifeAwasinitiallycallingveryfewVIAspositive.Bythetimeshehasperformed
500VIAsshewascallingout20%positive.Theproportionpositivefellsharplytoabout8%
after1000examinationsandthenroseslowlytoabout19%with2000examinations.Beyond
2000theproportionfellbackslightlytoabout15%.Thedifferentpatternsofthesmoothed
curvesconfirmedthevariationofVIAresultsandsuggestedthatthisvariabilitycouldnotbe
explainedbythenumberofVIAsperformed.Noevidenceforalearningcurveoraminimal
numberofVIAsneededtoachieveproficiencywasobserved.
Discussion
WehaveclearlydemonstratedthatmostofthevariationinVIAPRsinTATImaybeattributed
tolackofconsistencyininterpretation.Therewassubstantialvariabilityintheproportionof
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examinationscalledpositivebymonthandbymidwifewhoperformedthetestinC-TATI;in
contrastHR-HPVtestingresultswereconsistentlyhomogeneous.Theseresultssuggestedthat
thevariationinVIAPRswasnotduetodiseasevariation(1.6%overallrateofCIN2+,range:
1.0–4.4,D=0.20)buttothesubjectivenatureofthetest.
Surprisingly,despitethefactthatthe19C-TATImidwivesscreenedwomeninC-TATIand
inR-TATIinparallel,theoverallPRofVIAperformedbytheminC-TATI(24.2%)wastwice
thePRwhentheyscreenedwomeninR-TATI(13.7%).Indeed,18of19VIAPRsinC-TATI
werehigherthaninR-TATIduringthefirst11monthsoftheintervention.Onepotentialex-
planationforthesedifferencescouldbebleedingofthecervixassociatedtoadditionalsampling
(LBCandHPVafterPap)inC-TATI.Thebleedingandthehighprevalenceofvaginalinfec-
tionsmayhaveinterferedwiththevisualisationofthetransformationzone,affectingVIAper-
formance,despitethis,VIAresultsinC-TATIweresimilartothoseofotherstudies[7,15–19].
TheminimalnumberofVIAsandtheaveragemonthlyrateofVIAsthataproviderneeds
toachieveVIAproficiencyhavenotyetbeendetermined[2].Onfirstinspection,ouranalysis
suggestedthatasthenumberofVIAsperformedincreases,theexaminergetsmoreexpertise
onthetest,isabletobetterdistinguishaceto-whitelesionswithhigherlikelihoodofbeingtrue
lesions,andgrantslessfalsepositiveresults(Fig.3).Thiswasreinforcedbysimilarpatternsof
variationamongVIAresultsofthe19C-TATImidwivesinC-TATI(Fig.3a)andthoseofthe
23R-TATImidwivesinR-TATI(Fig.3b).However,whenweplottedtheproportionofVIA
positiveresultsofmidwiveswhoatleastperformed500exams,therewerenoconsistentpat-
ternsofVIAPRs,contradictingourpreviousobservationsandthatofalearningcurveofVIA
afterinitialtraining[19].
Similarlytopreviousstudies,thehighvariabilityofVIAresultspermidwifewasnotex-
plainedbylackofadequateanduniformtraining[18,20–23].Inourstudy,midwiveswerein-
tensivelytrainedoveraweekinwhichtheyperformedVIAunderrigoroussupervision.
Furthermore,wheneverwomenhadhigh-gradecytologyandnegativeVIA,theywerere-
examinedbythemidwifeandanexpertgynaecologisttogetherandreasonsfornotvisualising
lesionswerediscussed.
Ourstudyhassomelimitations.First,wewerenotabletocontrastpositivityrateswithdis-
easeascertainmentinR-TATIbecauseonlyPapandVIAwereusedtoreferwomenandun-
doubtedlyseveralcasesofCIN2+weremissed.However,weperformedthiscomparison
withinC-TATIandweshowedthatthehighvariationofVIAresultswasnotduetodisease
variationbuttohumanjudgement.Second,midwivesstartedperformingVIAatdifferenttime
pointsinTATIandonlyfourmidwivesperformedVIAeachmonthofTATI,possiblyaffecting
thelikelihoodofachievingproficiency.However,weevaluatedthevariationofVIAresultsper-
formedinamonthpermidwifeamongmidwiveswhoatleastperformed500examinations,
andfoundnoconsistentpatternamongtheproportionofVIApositiveresultsofmidwives.
Clearly,thestrongestevidencewouldhavecomefromhavingmultiplemidwivesexamining
eachwomanblindedtoeachother’sopinionorbyassigningwomentomidwivesatrandom.
Neitherofsuchoptionswaspractical,andsowehavereliedonanalysisofdatathatcouldbe
subjecttoconfounding.Nevertheless,ourstudyisthefirsttocomparetheVIAresultsof42
midwiveswhoaltogetherperformedmorethan36000VIAswithintheirroutineclinicalactivi-
tiesinalow-resourcesetting,andtheresultsarerobusttothemethodofanalysisandarelikely
toreflecttruevariation.
Despiteinconsistentresultsonitsperformance,VIAisusuallythemainscreeningtechnique
inuseinlow-resourcesettings,partlybecauseitistheonlysimplelow-costtestavailableand
partlybecauseVIAresultsareknownimmediatelyallowingsee-and-treatschemes.NewHR-
HPVlow-costtestsmaysoonbecomeavailableandHPV-and-treatorHPV-VIA-and-treat
schemesarealreadybeingconsideredaspotentialalternativestoVIA-and-cryotherapy.The
PLOSONE|DOI:10.1371/journal.pone.0115355 January30,2015 10/12